The European Commission's Joint Research Centre (JRC) produces reference materials that are tailored to meet the needs of European policy in various fields including health applications. Certified Reference Materials (CRMs) for In-Vitro Diagnostics (IVD) are essential for the development of reference systems for the standardisation of routine IVD measurements and their use is required by the IVD Regulation (EU) 2017/746. Protein biomarkers are prime targets for standardisation efforts due to their importance in diagnostics and health care and the typically observed significant discrepancies in measurement results obtained without standardisation. The standardisation process is often complicated by the heterogeneous nature of the analyte in terms of fragmentation, modification, substitution, primary, secondary, tertiary and quaternary structure. The approach of the JRC starts with the assessment of the state of the art for a particular analyte. Correlation studies, in which sets of single patient samples are measured with the main routine methods, will show the degree of variability between the methods. These studies will also provide information on the degree of standardization that can be achieved for the existing routine methods. The development of a CRM for protein biomarkers requires investigations on several parameters such as the availability of raw materials, commutability, stability, the level of the analyte of interest, and the strategy for assigning a certified value. In the recent years, the JRC has produced CRMs for several protein biomarkers in various clinical fields. Examples are: - ERM-DA480/IFCC, ERM-DA481/IFCC and ERM-DA482/IFCC are a panel of three pooled liquid frozen cerebrospinal fluid materials with different levels of amyloid-β 1-42 (Aβ1-42) which is a biomarker for the early detection of Alzheimer's disease. - ERM-DA483/IFCC was produced from plasmapheresis sample of a patient diagnosed with the auto-immune disorder called vasculitis. This material is certified for the mass concentration of the immunoglobin G proteinase 3 anti-neutrophil cytoplasmic autoantibodies (IgG PR3 ANCA). - ERM-AD456/IFCC was certified for the catalytic activity concentration of alphaamylase using the primary reference measurement procedure as established by the IFCC.